Process and intermediates for the preparation of indoles from ortho-nitrotoluenes

ABSTRACT

Ortho-nitrotoluenes are condensed with formamide acetals to yield the corresponding ortho-nitro- Beta -aminostyrenes which undergo cyclization upon reduction to yield indoles.

ilniied States Patent [19 1 Batcho. et al.

[54] PROCESS AND INTERMEDIATES FOR THE PREPARATION or INDOLES FROMORTHO-NITBOTOLUENES [75] Inventors: Andrew David Batcho, Belleville,Willy Leimgruber, Montclair, both of NJ.

Roche Nutley, NJ.

[22] Filed: NOV. 4, 1970 [21] Appl. No.2 86,953

Related [1.8. Application Data [63] Continuation-impart of Ser. No.876,619, Nov.

24, 1969, abandoned.

[52] US. Cl ..260/3l9.1, 260/240 D, 260/2409,

- 260/576 [51] lint. Cl. ..C07d 27/56 [151 3,732,245 [451 May8,1973

Primary ExaminerAlex Mazel Assistant Examiner-Joseph A. NarcavageAtt0rneySamuel L. Welt, Jon S. Saxe, Bernard S. Leon, William G. Isgroand Margaret C. Bogosian [57] ABSTRACT Ortho-nitrotoluenes are condensedwith formamide acetals to yield the corresponding 0rtho-nitro-,Baminostyrenes which undergo cyclization upon reduction to yield indoles.

16 Claims, N0 Drawings PROCESS AND INTERMEDIATES FOR THE PREPARATION OFINDOLES FROM ORTHO- NITROTOLUENES CROSS REFERENCE TO RELATEDAPPLICATIONS This application is a continuation-in-part of US. Pat.

application Ser. No. 879,619 filed Nov. 24, 1969 and now abandoned.

BRIEF SUMMARY OF THE INVENTION -reducing the resultingortho-nitro-B-aminostyrene to yield the corresponding indole.

In another aspect, the invention relates to the intermediateortho-nitro-B-aminostyrenes.

DETAILED DESCRIPTION OF THE INVENTION The invention comprises a processand intermediates for preparing indole and substituted indoles.

More particularly, the invention comprises condensing a formamide acetalwith an ortho-nitrotoluene to yield as an intermediate the correspondingorthonitro-B-aminostyrene and reducing said intermediate to yield thecorresponding indole.

As used herein, the term lower alkyl denotes a straight or branchedchain saturated hydrocarbon containing one to seven carbon atoms, forexample, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, neopentyl,pentyl, heptyl, and the like. The term lower alkoxy denotes an alkylether group in which the lower alkyl group is as described above, forexample, methoxy, ethoxy, propoxy, pentoxy, and the like. The termhalogen denotes thefour halogens, i.e., bromine, chlorine, fluorine, andiodine. The term aryl denotes phenyl or phenyl bearing one or moresubstituents selected from the group consisting of halogen,trifluoromethyl, lower alkyl, lower alkoxy, nitro, amino, loweralkylamino, and di-lower alkylamino. The term aryloxy" denotes an arylether group in which the aryl group is as described above, for example,phenoxy and the like. The term acyl" denotes an alkanoyl" group derivedfrom an aliphatic carboxylic acid of one to seven carbon atoms, forexample, formyl, acetyl, propionyl, and the like; and an aroyl groupderived from an aromatic carboxylic acid, such as benzoyl and the like.The term acyloxy denotes an alkanoyloxygroup derived from an aliphaticcarboxylic acid of l to 7 carbon atoms, for example, formylox- 'y,acetoxy, propionyloxy, and the like; and an aroyloxy group derived froman aromatic carboxylic acid, such as benzoyloxy and the like. The termlower alkylenedioxy denotes an alkylene diether group having from one toseven carbon atoms such as methylencdioxy, cthylenedioxy,propylenedioxy, and the like. The term lower alkylene denotes ahydrocarbon radical of two to five carbon atoms, such as ethylene,propylene, butylene, and pentylene; preferred are those of two to threecarbon atoms. The term ar-alkyl denotes a lower alkyl group in which oneor more of the hydrogen atoms have been replaced by an aryl group.Exemplary is benzyl. The term cycle-alkyl denotes a cyclic hydrocarbonof three to six carbon atoms, for example, cyclopentyl and the like.

Exemplary of aryl-lower alkoxy groups are benzyloxy, l-phenylethyloxy,2-chlorobenzyloxy, and the like. Exemplary of aryl-hydroxymethyl groupsare phenylhydroxymethyl, p-chlorophenylhydroxymethyl, and the like.Exemplary of lower alkoxy-carbonyl groups are methoxycarbonyl,ethoxycarbonyl, andthe like. Exemplary of mono-lower alkylamino groupsare methylamino, ethylamino, propylamino, isopropylamino, butylamino,pentylamino, and the like. Exemplary of di-lower alkylamino groups aredimethylamino, diethylamino, ethylmethylamino, dipropylamino, and thelike. Exemplary of lower alkoxycarbonylamino groups aremethoxycarbonylamino, ethoxycarbonylamino, and the like. Exemplary ofaryl-lower alkoxycarbonylamino groups are benzyloxycarbonylamino,p-chlorobenzyloxycarbonylamino, and the like. Exemplary of acylaminogroups are formamino, acetamino, propionylamino,

benzoylamino, and the like. Exemplary of N-lower alkylacylamino groupsare N-methylacetamino, N-

methylformamino, N-ethylacetamino, and the like. Ex-

emplary of di-lower alkylformamidino groups are dimethylformamidino,diethylformamidino, and the like.

In a preferred embodiment, the process of the invention is characterizedby reaction scheme I:

I" Reaction Scheme I 7 R2 R u wherein R R., R, and R independently, areselected from the group consisting of hydrogen, lower alkyl, aryl,hydroxy, lower alkoxy, aryl-lower alkoxy, aryloxy, acyloxy, formyl,aroyl, hydroxymethyl, aryl-hydroxymethyl, carboxy, lower alkoxycarbonyl,carbamoyl, halogen, cyano, amino, mono-lower alkylamino, diloweralkylamino, lower alkoxycarbonylamino, aryllower alkoxycarbonylamino,acylamino, N-lower alkylacylamino, di-lower alkyl-formamidino, di-loweralkoxymethyl, or nitro; R and R or R, and R or R and R when takentogether, are lower alkylenedioxy; R and R independently, are loweralkyl, and when taken together, are lower alkylene; and R and Rindependently, are lower alkyl and when taken together, are loweralkylene.

In a more preferred embodiment, the process of the invention ischaracterized by reaction scheme II:

Reaction Scheme II l condensation Preferably, R and R independently, arehydrogen,

lower alkyl, hydroxy, lower alkoxy, aryl-lower alkoxy,

acyloxy, formyl, aroyl, halogen, cyano, nitro, amino, or acylamino, andwhen taken together are lower alkylenedioxy; and R R R and Rindependently, are

- lower alkyl, and R and R or R and R when taken together, are loweralkylene.

In a most preferred embodiment of the invention, 0- nitro-toluene iscondensed with N,N-dimethylformamide dimethyl aceta] to yieldtrans-,B-dimethylamino-Z- nitrostyrene. The latter is hydrogenated toyield indole.

In a further aspect, the invention relates to intermediatescharacterized by the formula Iva wherein R R R and R1, independently,are hydrogen, lower alkyl, lower alkoxy, aryl, formyl, aroyl, hydroxy,aryl-lower alkoxy, aryloxy, acyloxy, hydroxymethyl, aryl-hydroxymethyl,carboxy, lower alkoxycarbonyl, carbamoyl, halogen, cyano, amino,monolower alkylamino, di-lower alkylamino, lower alkoxycarbonylamino,aryl-lower alkoxycarbonylamino, acylamino, N-lower alkylacylamino,di-lower alkyI-formamidino, or di-lower alkoxymethyl; R and R R and R Rand R when taken together, are lower alkylenedioxy; and R and R are aspreviously described.

In a further aspect, the invention relates to the intermediatescharacterized by the formula wherein R, and R independently, arehydrogen, lower alkyl, lower alkoxy, aryl, formyl, aroyl, hydroxy,aryl-lower alkoxy, aryloxy, acyloxy, hydroxymethyl, aryl-hydroxymethyl,carboxy, lower alkoxy-carbonyl, carbamoyl, halogen, cyano, amino,mono-lower alkylamino, di-lowcr alkylamino, lower alkoxycarbonylamino,aryllower alkoxycarbonylamino, acylamino, N-lower alkylacylamino,di-lower alkyl-formamidino, or dilower alkoxymethyl; R, and R when takentogether, are lower alkylenedioxy; and R and R are as previouslydescribed.

Preferably, in formula IVa, R, and R independently, are hydrogen,hydroxy, lower alkyl, lower alkoxy, formyl, aroyl, cyano, acyloxy,aryl-lower alkoxy, halogen, amino, or acylamino, and when takentogether, are lower alkylenedioxy; and R and R independently, are loweralkyl.

It will be appreciated that the ortho-nitro-B- aminostyrenes of formulasIV, IVa, IVa' and IVa" have the trans-configuration.

As is evident from the above, the present invention relates to a novelpreparative route to indoles. It provides to the art a new andsignificant reaction route to many compounds of commercial value. Theprocess is particularly salient in providing such compounds with greaterefficiency than heretofore known in the prior art.

Broadly stated, the novel preparative path herein disclosed involvescondensing the methyl function of an ortho-nitrotoluene with the formylgroup of a formamide acetal, whereby a nitrobenzene derivative isobtained which bears a N,N-di-substituted aminovinyl function ortho tothe nitro group, and thereafter by reducing the nitro group to an aminogroup which concurrently displaces the N,N-di-substituted amino functioneffecting cyclization to a compound having an indole nucleus.

The ortho-nitrotoluenes are known compounds or can be prepared by knownprocedures. Such compounds have monocyclic or bicyclic structures whichmay contain hetero atoms. Further, they may be unsubstituted orsubstituted independently with up to 4 moieties such as lower alkyl,aryl, hydroxy, lower alkoxy, aryl-lower alkoxy, aryloxy, acyloxy,formyl, aroyl, hydroxymethyl, arylhydroxymethyl, carboxy, loweralkoxycarbonyl, carbamoyl, halogen, cyano, nitro, amino, mono-loweralkylamino, di-lower alkylamino, lower alkoxycarbonylamino, aryl-loweralkoxycarbonylamino, acylamino, N-lower alkylacylamino, di-loweralkylformamidino or dilower alkoxymethyl; or with up to 2 moieties oflower alkylenedioxy. Examples of such compounds are3-methyl-4-nitrobiphcnyl, 2-methyl-3- nitrobenzyl alcohol,3-nitro-p-toluamide, 4-methyl-3- nitrobenzophenone, 3-nitro p-toluicacid methyl ester, N,N-dimethyl- 3-nitro-p-toluidine, 3-nitro-p-toluicacid, 4-methyl-3-nitrobenzophenone, N-methyl-3- nitro-p-toluidine,3-nitro-p-toluidine, and the like.

The formamide acetals are known compounds or can be prepared by knownprocedures. Preferred formamide acetals are, for example,N,N-dimethylformamide diethyl acetal, N,N-dimethylformamide dimethylacetal, N-formylpyrrolidine dimethyl acetal, 2-

such as, for example, N,N-dimethylformamide'(DMF), l

diethyleneglycol dimethyl ether (Diglyme), hexamethylphosphortriamide(HMPT), and the like. The reaction conditions for the condensation arenot narrowly critical. Thus, the condensation can be conducted at atemperature in the range of between about room temperature and thereflux temperature of the reaction mixture. Preferably, the reaction isconducted at a temperature in the range of 100-160. Most conveniently,the reaction is conducted at the reflux temperature of the reactionmixture. The condensation may be effected at atmospheric orsuper-atmospheric pressures. Conveniently, it is effected at atmosphericpressure.

The compounds of formulas Na and Na" are novel compounds. In accordancewith the invention, the ortho-nitro-,8-aminostyrene intermediates, e.g.,of formula IV or lVa, hereinafter referred to as aminostyrenes, arereduced chemically or catalytically to yield the corresponding indoles,e.g., of formula I or la. The catalytic reduction may be effected in anyconventional manner; preferably, it is effected at about roomtemperature with a hydrogen pressure of from about 1 to about 10atmospheres. Any suitable hydrogenation catalyst may be employed, forexample, a metal selected from the group consisting of chromium,molybdenum, tungsten, platinum, palladium, rhodium, cobalt, nickel, andruthenium, their oxides, and combinations thereof, for instance, theoxides of cobalt or molybdenum in admixture and including cobaltmolybdate. The preferred hydrogenating component is palladium, as wellas other platinum group metals, or Raney nickel. Conveniently, thecatalyst may be supported on charcoal, carbon or the like.

Advantageously, the catalyst may be utilized in the presence of an inertsolvent, for example, an alkanol such as methanol, ethanol, and thelike, a hydrocarbon such as benzene, toluene and the like; ethylacetate; and DMF. Most preferably, benzene is utilized.

The chemical reduction may be effected in a conventional manner, forexample, with a metal such as iron, zinc, tin, and the like, in anorganic or inorganic acid such as acetic acid, hydrochloric acid, andthe like; stannous chloride in hydrochloric acid, ferrous sulfate;sodium dithionite; sodium or ammonium sulfide or hydrosulfide; and thelike. The reaction conditions for the chemical reduction are notcritical. Preferably, it is effected at a temperature in the range ofbetween about room temperature and reflux temperature of the reactionmixture, in the presence of a solvent such as water, or water'rnisciblesolvents, for example, alkanols such as methanol, ethanol or the like,or tetrahydrofuran.

While the substituents represented by R,, R R and R generally do notundergo a change during the condensation and subsequent reduction, incertain cases changes may occur. For instance, during the condensation,a carboxyl group may be converted to an ester group and a phenolichydroxyl group may be converted to a phenolic ether. A dialkoxymethylgroup can be retained or hydrolyzed depending on the work up. Thus, inthe presence of acid, the dialkoxymethyl group is cleaved, and if noacid is present, it is retained.

Upon completion of the reaction, if desired, the end products, forexample, indole, may be recovered utilizing conventional means such ascrystallization, distilla tion or steam distillation and the like. Theclass of products resulting from the process of the invention, i.e.,indole and the substituted indoles exemplified by formula 1 are welldocumented in the literature and are useful for many purposes, forexample, as intermediates in the preparation of amino acids, alkaloids,tryptamines, and the like. Thus, for example, indole, 6- methoxyindole,and S-benzyloxyindole can be utilized as intermediates in thepreparation of tryptophan, reserpine, and serotonin, respectively, etc.

The following examples further illustrate the invention. Alltemperatures are in Centigrade degrees unless otherwise indicated.

EXAMPLE 1 Preparation of trans-B-dimethylamino-Z-nitrostyrene A l-literthree-necked flask fitted with a thermometer, a 15-cm. Vigreux columnconnected to a descending condenser and a receiver with a nitrogen inletwas charged with 137 g. of o-nitrotoluene, 191 g. of N,N-dimethylformamide diethyl acetal, and 235 ml. of N,N- dimethylformamide.The flask was immersed in a preheated oil bath which was maintained at165 for 24 hours. The pot temperature was maintained at -l 5 0 bycontinuous distillation of the formed ethanol.

The volatile components were removed by vacuum distillation under anatmosphere of nitrogen. The remaining dark red liquid was thentransferred to a flask and distilled to yield 186 g. (97 percent) oftrans- B-dimethylamino-Z-nitrostyrene as a dark red liquid having aboiling point of l25/0.03 mm.

Anal. Calcd. for C H N O C, 62.48; H, 6.29; N, 14.58 Found: C, 62.66; H,6.63; N, 14.50

EXAMPLE 2 Preparation of .trans-B-dimethylamino-2-nitrostyrene In a1-liter three-necked flask fitted with a thermometer, a vacuum-jacketed,silvered column with Goodloe packing, distillation head and a receiverwith a nitrogen inlet were placed 137.] g. of o-nitrotoluene, 121.6 g.of 98 percent N,N-dimethyl-formamide dimethyl acetal, and 200.0 g. ofN,N-dimethylforma mide (DMF). The reaction mixture was heated at refluxfor 24 hours. The reaction temperature was maintained at l35-l55 bycontinuous distillation of the methanol as fonned. A total of 56.0 g. ofdistillate was collected.

By careful distillation 206.3 g. of DMF, b.p. 51- 55/20 mm., and 13.0 g.(10 percent) of o-nitrotoluene, b.p. l09l23 mm., were removed from thereaction mixture to give a residual dark liquid which after distillationyielded 167.0 g. (87 percent) of trans-B dimethylamino-Z-nitrostyrene asa dark red liquid having a boiling point of l28 /0.05 mm.

EXAMPLE 3 Preparation of trans-B-dimethylamino-2-nitrostyrene A solutionof 27.4 g. of o-nitrotoluene and 31.2 g. of 95 percentN,N-dimethylformamide diethyl acetal was heated under a nitrogenatmosphere in a 165 oil bath for 22 hours with continuous distillationof the ethanol formed in the reaction through a distillation head anddescending condenser.

The volatile components were removed by vacuum distillation and then20.2 g. (52 percent) of trans-B- dimethylamino-2-nitrostyrene wascollected at boiling point l27-29/0.08 mm.

EXAMPLE 4 Preparation of trans-B-dimethylamino-2-nitrostyrene A 50-ml.glass liner containing 15.6 g. of 95 percent dimethylformamide diethylacetal and 13.7 g. of onitrotoluene was pressurized with nitrogen in anautoclave to 35 atm. and then heated to 155 for 24 hours.

The resulting red solution was distilled from a 50-ml. Claisen flask.The forerun (b.p. up to 60/0.2 mm.) was discarded. The red liquiddistilling at 134-l36/0.25 mm. amounted to 13.4 g. (70 percent) oftrans-B- dimethylamino-2-nitrostyrene.

EXAMPLE 5 Preparation of indole from trans-B-dimethylamino-Z-nitrostyrene A solution containing 178.6 g. of trans-B-dimethylamino-2-nitrostyrene in 2.5 liters of benzene containing 2.0 g.of percent palladium on carbon was shaken in a 4-liter autoclave underan initial hydrogen pressure of 4.5 atm. until the absorption ofhydrogen ceased. The catalyst was removed by filtration and was washedseveral times with benzene. The benzene solution was then extracted with3 X 600 ml. of 1N sulfuric acid and 2 X 500 ml. of water. The aqueousphases were back-washed in a countercurrent manner with 500 ml. ofbenzene. The combined benzene phases were dried over a mixture ofanhydrous sodium sulfate and potassium carbonate, filtered, andevaporated to give 96.0 g. of greyish solid, which on rapid distillationunder nitrogen gave 91.3 g. of a slightly yellowish solid having amelting point of 51-53 The distillate, on fractionation, gave a total of87.4 g. (80 percent) of indole as a white solid having a melting pointof 52.5 53.5.

EXAMPLE 6 Preparation of indole by reduction of trans-B-dimethylamino-2-nitrostyrene with iron and acetic acid In a 500-ml.three-necked flask fitted with a thermometer and mechanical stirrer wereplaced 19.2 g. of trans-B-dimethylamino-2-nitrostyrene, 100 ml. of 28ethanol, and 100 ml. of glacial acetic acid followed by 41.9 g. of ironpowder over a 5-min. period. The suspension was stirred for 2 hoursduring which time the temperature rose to 45 (the temperature wascontrolled by a water bath); then 30 ml. of 1N hydrochloric acid wasadded. The red color discharged and the temperature rose to about 45.The reaction was allowed to stand for 18 hours and then was poured onto1 l. of ice-water. To the resulting slurry was added 250 ml. of benzene;then both phases were filtered through a diatomaceous silica bed. Thebenzene layer was separated and the aqueous layer extracted once morewith 200 ml. of benzene. The combined benzene extracts were washedsuccessively with 2 X 200 ml. of 0.5N H 4 and ml. of 10 percent K CO Theaqueous phases were backwashed in a countercurrent manner with 100 ml.of benzene. The combined organic phases were dried (Na SO filtered, andevaporated to give 4.2 g. of a brown solid which was dissolved in aminimum amount of benzene and was chromatographed on 50 g. of alumina(Woelm, activity 111). Eluted fractions containing indole (pet.etherbenzene, 9:1) were pooled according to thin layer chromatography.Evaporation of the solvents and sublimation of the residue (4050 oilbath/0.03 mm.) yielded 2.02 g. (17 percent) of indole as white plateshaving a melting point of 5 l .5-52.5

EXAMPLE 7 Preparation of indole by reduction of trans-B-dimethylamino-2-nitrostyrene with sodium dithionite To a stirredsolution of 19.2 g. of trans-B- dimethylamino-Z-nitrostyrene in 500 ml.of water and 200 ml. of methanol was added portionwise over 5 min. amixture of 55.0 g. of sodium dithionite and 28.0 g. potassium carbonatewhile maintaining the temperature at 6065 by a water bath. A suspensionformed; so 300 ml. of methanol was added and stirring was continued for0.75 hour. To this were added 20 ml. of 30 percent ammonium hydroxideand, after removal of the methanol with a rotary evaporator, anadditional 60 ml. of 30 percent ammonium hydroxide. The solution wasthen extracted with 3 X 400 ml. of benzene. The organic phases werebackwashed in a counter-current manner with 100 ml. of water. Thecombined organic phases were dried (Na SO filtered, and evaporated togive 3.5 g. of a dark brown solid which was dissolved in a minimumamount of benzene and chromatographed on 60 g. of alumina (Woelm,activity 111). Eluted fractions (pet. ether) containing indole werepooled according to thin layer chromatography. Evaporation of thesolvents and sublimation of the residue (2.4 g.) yielded 2.14 g. (18percent) of indole having a melting point of 50-52.

EXAMPLE 8 Preparation of trans-2-nitro-B-pyrrolidinostyrene In a 100-ml.three-necked flask fitted with a thermometer and 8-cm. Vigreuxdistillation head connected to a descending condenser and receiver witha nitrogen inlet were placed 6.85 g. of o-nitrotoluene, 7.25 g. ofN-formylpyrrolidine dimethyl acetal, and 25 ml. ofN,N-dimethylformamide. The flask was immersed in 160 oil bath for 1 hourduring which time 2.8 ml. ofmethanol distilled. Volatile components wereremoved by vacuum distillation from a Claisen flask. A portion of theresidue was distilled with partial decomposition in a short pathdistillation flask (bath l50/0.1 mm.). The distillate was then vaporizedtwice in a molecular still (bath /0.04 mm.), discarding a small amountof fore-run each time. In this way, 560 mg. oftrans-2mitro-B-pyrrolidinostyrene was obtained as a red liquid.

Anal.

Calcd. for C I-1. 191 1 Found:

EXAMPLE 9 Preparation of indole via rolidinostyrene To a 100-ml.three-necked flask fitted with a thermometer and 8-cm. Vigreux columnconnected to a descending condenser and receiver with a nitrogen inletwas added 13.7 g. of o-nitrotoluene, 16.0 g. of N- formylpyrrolidinedimethyl acetal, and 50 ml. of N,N- dimethylformamide. The solution wasthen heated to 130150 for 1.5 hours, maintaining the temperature bycontinuous distillation of the methanol which formed in the reaction.

Removal of the volatile components by vacuum distillation (bath 50/1mm.) gave trans-Z-nitro-B-pyrrolidinostyrene asa red liquid.

The product was dissolved in 100 ml. of benzene and was shaken in ahydrogen atmosphere with 440 mg. of percent palladium on charcoal at aninitial pressure of 3.5 atm. until hydrogen absorption ceased (3equivalents). The catalyst was removed by filtration through a bed ofdiatomaceous silica and was washed with 3 X 50 ml. of benzene. Thefiltrate was then extracted consecutively with 2 X 200 ml. of 1Msulfuric acid, 2 X 200 m1. of water, and 100 ml. of 1M sodium carbonate.The aqueous phases were backwashed in a counter-current manner with 2 X200 ml. of benzene. The combined organic phases were dried (Na SOfiltered, and evaporated (rotary evaporator) to give 1 1.0 g. ofgreenish solid, which on distillation gave 9.61 g. (82 percent) ofindole, boiling point 78/0.3 mm., melting point 505 l .5.

trans-2-nitro-B-pyr- EXAMPLE 10 Preparation oftrans-2-nitro-B-piperidinostyrene In a 100 ml. three-necked flask fittedwith a thermometer and 8-cm. Vigreux distillation head connected to adescending condenser and receiver with a nitrogen inlet were placed 6.85g. of o-nitrotoluene, 8.76 g. of N-formypiperidine dimethyl acetal, andml. of N,N-dimethylformamide. The flask was immersed in a 150 oil bathfor 7 hours during which time 4 ml. of methanol distilled. Vacuumdistillation from a Claisen flask afforded, after removal of thevolatile components, three fractions: 2.86 g. (b.p. 144-145 /0.06 mm),0.73 g. (b.p. l45-146/0.06 mm.), and 5.35 g. (b.p. 146l47/0.07 mm.). Thelast fraction was pure trans-Z-nitro-B-piperidinostyrene.

Anal. Calcd. for C H MO I Found:

EXAMPLE 1 1 to distill as it formed. Removal of the volatilecomtrans-2-nitro-B- ponents by vacuum distillation (water bath at 60/0.5

mm.) gave trans-Z-nitro-B-piperidinostyrene as a red liquid.

The trans-2-nitro-B-piperidinostyrene was dissolved in 250 ml. ofbenzene, 0.460 g. of 5 percent palladium on charcoal was added, and thesuspension was shaken under an initial hydrogen pressure of 3.5 atm.until the absorption of hydrogen ceased (3 equivalents). The catalystwas removed by filtration and was washed several times with benzene. Thefiltrate was extracted with 3 X 100 ml. of 1M sulfuric acid, 100 ml. ofwater, 2 X 100 ml. of 1N sodium hydroxide, and 100 ml. of water. Theaqueous phases were back-washed in a counter-current manner with 100 ml.of benzene. The combined organic phases were dried (Na SO filtered, andevaporated to give 9.06 g. of a brown solid. Distillation in a Claisenflask gave 7.66 g. percent) of indole, boiling point 6065/0.06 mm.,melting point 44-49.

EXAMPLE 12 trans-fi-dimethylamino-2,4-

(200 ml.) to yield 19.54 g. (82 percent) of trans-B-dimethylamino-2,4-dinitrostyrene as dark violet crystals having amelting point of 172.5 "-174".

EXAMPLE 13 Preparation of 6-aminoindole A solution containing 4.75 g. oftrans-B- dimethylamino-2,4-dinitrostyrene in 250 ml. ofethanol-N,N-dimethylformamide (4:1) was shaken with a teaspoonful ofRaney nickel in a Parr apparatus under an initial hydrogen atmosphere of3.5 atm. until hydrogen absorption ceased. The catalyst was removed byfiltration through a bed of Celite* diatomaceous silica) and washed withethanol. The filtrate and washings were dried on a rotary evaporator.The residue was filtered in benzene through a dry column of 25 g. ofFlorisil** magnesia silica gel) and the fractions containing the productwere combined. The material was sublimed at 60/0.05 mm. to give 600 mg.(23 percent) of 6-aminoindole as a white solid having a melting point of77.5-78.5.

Anal. Calcd. for C,H,N,: C,72.7l; H,6.l0;N,2l.l9 Found: C, 72.50; H,6.24; N, 2l.28

EXAMPLE 14 Preparation of 5-benzyloxy-2-nitrotoluene To a solutioncontaining 15.3 g. of 3-methyl-4- nitrophenol in 200 ml. absoluteethanol stirred under nitrogen, 5.40 g. of sodium methoxide were addedover a period of 15 minutes. The solution was then stirred at reflux for1.5 hours. Thereafter, 12.66 g. of benzyl chloride were added dropwise,and the reaction was maintained at reflux for 20 hours. The ethanol wasevaporated from the reaction mixture. To the residue were added 200 ml.of ether and ml. 1N sodium hydroxide. The ether solution was washed withan additional 100 ml. of 1N sodium hydroxide solution and then with 100ml. of water. The aqueous phases were washed with ether (3 X 300 ml.) ina counter-current manner. The combined aqueous phases were acidifiedwith phosphoric acid and extracted with methylene chloride (3 X 200ml.). The combined methylene chloride layers were dried (Na SO andevaporated to dryness to give 2.8 g. (18 percent) of recovered 3-methyl-4-nitro-phenol. The ether extracts were dried (Na SO andevaporated to dryness. The aqueous phases were discarded and the organicphases dried (Na SO and evaporated to dryness. The product wascrystallized from methanol (75 ml.), yielding 15.1 g. (62 percent of5-benzyloxy-2-nitro-toluene as white needles having a melting point of70.571.5.

EXAMPLE Preparation of trans-5-benzyloxy-B-dimethylamino-2- nitrostyreneA 100-ml. three-necked flask fitted with a thermometer and a 15-cm.Vigreux column connected to a descending condenser and a receiver with anitrogen inlet was charged with 24.32 g. of 5-benzy1oxy-2- nitrotoluene,23.0 g. of N,N-dimethylformamide diethyl acetal, and 25 ml. ofN,N-dimethylformamide. The reaction vessel was then immersed in a 160oil bath for 40 hours. The pot temperature was maintained above 140 bycontinuous distillation of the ethanol as it was formed.

The volatile components were removed under reduced pressure on a rotaryevaporator. The red solid residue, crystallized from 300 ml. of etherand 25 ml. of benzene, yielded 23.3 g. (78 percent) of trans-5-benzyloxy-B-dimethylamino-2-nitrostyrene as red needles having a meltingpoint of 97.5-99.

Anal.

Calcd. for C,,H,,N,0,; C, 68.44; H, 6.08; N, 9.39 Found: C, 68.73; H,6.13; N, 9.46

EXAMPLE 16 Preparation of S-benzyloxyindole A solution containing 15.0g. of trans-S-benzyloxy-B- dimethyl-amino-2-nitrostyrene in 250 ml. of80 percent ethanol-N,N-dimethylformamide and 1 teaspoonful of Raneynickel were shaken under a hydrogen atmosphere in a Parr apparatus untilhydrogen absorption ceased. The catalyst was removed by filtration. Thesolvents were removed under vacuum. The residue was sublimed and thesublimate was crystallized from ether-petroleum ether to yield 5.1 g.(45 percent) of 5- benzyloxyindole as white needles having a meltingpoint of l03-l05.

EXAMPLE 17 Preparation of trans-3(B-dimethylaminovinyl)-4- nitrobenzoicacid ethyl ester A 100-ml. three-necked flask fitted with a thermometerand a 15-cm. Vigreux column connected to a descending condenser and areceiver with a nitrogen inlet was charged with 18.1 g. of 3-methyl-4-nitrobenzoic acid, 37.6 g. of N,N-dimethylformamide diethyl acetal, and25 ml. of N,N-dimethylformamide. The reaction vessel was then immersedin a 100 oil bath for 4.5 hours. The pot temperature was maintainedabove 135 by continuous distillation of the ethanol formed in thereaction.

The volatile components were removed by vacuum distillation. Aftertrituration with petroleum ether, the residue crystallized to give 18.5g. percent) of trans-3-(B-dimethylaminovinyl)-4-nitrobenzoic acid ethylester as a red solid having a melting point of 55-56.5.

Anal. Calcd. for C H,,N,O C, 59.08; H, 6.10; N, 10.60 Found: C, 59.02;H, 6.00; N, 10.63

EXAMPLE 18 Preparation of S-indolecarboxylic acid ethyl ester A solutioncontaining 7.5 g. of trans-3-(B- dimethylaminovinyl)-4-nitrobenzoic acidethyl ester in 250 ml. of absolute ethanol and 715 mg. of 10 percentpalladium on carbon were shaken under 3.5 atm. of hydrogen in a Parrapparatus until hydrogen absorption ceased. The catalyst was removed byfiltration, and the filtrate was dried. The residue was applied to aFlorisil* magnesia silica gel) column (100 g.). The fractions containingthe product (eluted with benzene) were combined. Crystallization fromether-petroleum ether yielded 2.1 g. (39 percent) of 5-indolecarboxylicacid ethyl ester as white crystals having a melting point of 96.

Anal. Ca1cd.for C,.H,,N0,; c, 69.82; H, 5.86; N, 7.40 Found: C, 70.14;H, 5.87; N, 7.45

EXAMPLE 19 Preparation of trans-6-ch1oro-B-dimethy1amino-2- nitrostyreneA 250 ml. three-necked flask fitted with a thermometer and a 15-cm.Vigreux column connected to a descending condenser and receiver with anitrogen inlet was charged with 17.16 g. of 2-chloro-6- nitrotoluene, 24g. of N,N-dimethylformamide diethyl acetal, and ml. ofN,N-dimethylformamide. The reaction vessel was immersed in an oil bath,preheated to 160, for 6 hours. The pot temperature was maintained aboutby continuous distillation of the ethanol formed in the reaction.

The volatile components were removed by vacuum distillation at 25l3 mm.and the product was distilled to give 20.2 g. (89 percent) oftrans-6-chloro-B- dimethylamino-2-nitrostyrene as a dark red liquidhaving a boiling point of 1l1/0.03 mm.

Anal.

Calcd. for C H CIN,O,: C, 52.99; H, 4.89;

CI, 15.67; N, 12.36

Found: C, 53.18; H, 4.57

CI, 15.75 N, 12.23

EXAMPLE 20 Preparation of 4-chloroindole To a solution containing 10.40g. of trans-6-chlorofl-dimethylamino-Z-nitrostyrene in'250 ml. ofbenzene in a 500-ml. Parr bottle was added a half teaspoon of Raneynickel. The suspension was shaken under an initial hydrogen pressure of3.5 atm. until the absorption of hydrogen ceased. The catalyst wasremoved by filtration and was washed several times with benzene. Thebenzene filtrate was then extracted with 3 X 75 ml. of 1M sulfuric acidand 2 X 100 ml. of water. The aqueous phases were back-washed with 125ml. of benzene in a counter-current manner. The combined benzene phaseswere dried (K C0 filtered, and evaporated to give 5.4 g. of dark greenoil which, on distillation, yielded 4.75 g. of a yellow liquid having aboiling point of 1l6/2 mm. After redistillation there was obtained 4.41g. (63 percent) of 4-chlroindole as a slightly yellow liquid having aboiling point of 90/0.04 mm.

EXAMPLE 21 Preparation of trans-5-chloro-B-dimethylamino-2- nitrostyreneA 250-ml. three-necked flask fitted with a thermometer and a -cm.Vigreux column connected to a descending condenser and receiver with anitrogen inlet was charged with 34.3 g. of 5-chloro-2- nitrotoluene,55.0 g. of 85 percent N,N-dimethylformamide diethyl acetal, and 200 ml.of N,N-dimethylformamide. The reaction vessel was immersed in an oilbath, preheated to 160, for 7 hours. The pot temperature was maintainedabove 146 by continuous distillation of the formed ethanol.

The volatile components were removed by vacuum distillation (70 bath/0.5mm.). The resulting dark red residue was crystallized fromether-petroleum ether (275 ml.) to give 33.2 g. of red crystals having amelting point of 8l.5-82.5. From the mother liquor an additional 6.6 g.of crystals having a melting point of 7881 was obtained. Thus, the totalyield of trans-5- chloro-B-dimethylamino-2-nitrostyrene was 39.8 g.(88%).

Anal.

Calcd. for c u clmo C, 52.99; H, 4.89;

Cl, 15.64; N, 12.36 Found: C, 52.65; H, 5.20;

CI, 15.69; N, 11.89

EXAMPLE 22 Preparation of 5 -chloroindole To a solution of 11.6 g. oftrans-S-chloro-B- dimethylamino-2-nitrostyrene in 250 ml. of benzene ina 500-ml. Parr bottle was added a half teaspoon of Raney nickel. Thesuspension was shaken under an initial hydrogen pressure of 3.5 atm.until the absorption of hydrogen had ceased. The catalyst was removed byfiltration and was washed several times with benzene. The benzenefiltrate was then extracted with 2 X 100 ml. of 1N sulfuric acid, 2 X100 ml. of water, and 100 ml. of 10 percent sodium bicarbonate solution.The aqueous phases were back washed with 100 ml. of benzene in acounter-current manner. The combined benzene phases were dried (Na SOfiltered and evaporated to give 6.8 g. of greenish solid. Distillationyielded 6.26 g. of almost white solid which was dissolved in ether andpercolated through about a gram of alumina. After removal of the ether,the residue was crystallized from 30 ml. of petroleum ether to give 6.0g. (78 percent) of 5-chloroindole as white plates having a melting pointof 7172.

EXAMPLE 23 The volatile components were removed by vacuum distillationunder nitrogen until the head temperature began to rise to 158/0.09 mm.Subsequent distillation gave 12.0 g. (57 percent) of trans-4-chloro-B-dimethylamino-2-nitrostyrene as a red liquid having a boiling point ofl58/0.09 mm., which crystallized on standing to a solid having a meltingpoint of 44-46.

Anal.

Calcd. for C H CIN,O,: C, 52.99; H, 4.89;

CI, 15.63; N, 12.36 C, 52.96; H, 4.89; CI, 15.63; N, 12.30

EXAMPLE 24 Preparation of 6-chloroindole A solution of 4.50 g. oftrans-4-chloro-B- dimethylamino-2-nitrostyrene in 250 m1. of absoluteethanol and 1 teaspoonful of Raney nickel were shaken under a hydrogenatmosphere until hydrogen absorption ceased. The catalyst was removed byfiltration, and the filtrate was evaporated. The residue was applied toa Florisil column (25 g.). The fractions containing the product (elutedwith 5 percent benzene-hexane) were combined. Crystallization frombenzenehexane yielded 1.59 g. (52 percent) of 6-chloroindole as whitecrystals having a melting point of 8989.5.

EXAMPLE 25 trans-4-cyano-B-dimethylamino-2- Found:

Preparation of nitrostyrene A 500-m1. three-necked flask fitted with athermometer and a 15-cm. Vigreux column connected to a descendingcondenser and receiver with a nitrogen inlet was charged with 24.3 g. of3-nitro-p-tolunitrile, 33.9 g. of N,N-dimethylformamide diethyl acetal,and ml. of N,N-dimethylformamide. The reaction vessel was immersed in anoil bath, preheated to for 2.5 hours. The pot temperature was maintainedabove 140 by continuous distillation of the formed ethanol.

The volatile components were removed by vacuum distillation at 25/0.5mm. The resulting dark red solid residue was crystallized from 600 ml.of methanol, to yield 27.9 g. of trans-4-cyano-B-dimethylamino-2-nitrostyrene as red crystals having a melting point of 134137.5.

Anal. Calcd. for C"H"H,O,: C, 60.82; H, 5.10; N, 19.55 Found: C, 60.89;H, 5.10; N, 19.09

EXAMPLE 26 Preparation of 6-cyanoindole A solution containing 10.85 g.of trans-4-cyano-B- dimethyl-aminoi2-nitrostyrene in 500 ml. of benzenewas separated into two equal portions and to each was added 215 mg. ofpercent palladium on carbon. The suspensions were shaken under aninitial hydrogen pressure of 3.5 atm. until the absorption of hydrogenceased. The reaction was exothermic and was externally cooled with astream of air. The catalyst was removed by filtration and washed severaltimes with benzene. The benzene filtrates were combined and thenextracted with 2 X 100 ml. of 1M sulfuric acid, 2 X 150 ml. of water,and 150 ml. of 10 percent sodium bicarbonate solution. The aqueousphases were backwashed with 100 ml. of benzene in a counter-currentmanner. The combined benzene phases were dried (Na SO filtered, andevaporated to give 5.79 g. of solid which was dissolved in 150 ml. ofbenzene and filtered through 20 g. of alumina. After removal of thesolvent, the residue was sublimed (1l0/0.05 mm.) to give 5.39 g. ofwhite crystalline material which, after crystallization from 30 ml. ofbenzene-petroleum ether, yielded 4.57 g. (65 percent) of 6-cyanoindolehaving a melting point of 128129.

EXAMPLE 27 Preparation of 5 ,6-dimethylindole A 500-ml. three-neckedflask fitted with a thermometer and -cm. Vigreux column connected to adescending condenser with a receiver and nitrogen inlet was charged with33.0 g. of 5-nitropseudocumene, 48.3 g. of N,N-dimethylformamide diethylacetal, and 200 ml. of N,N-dimethylformamide. The reaction vessel wasimmersed in an oil bath, preheated to 165, for 31 hours. The pottemperature was maintained above 140 by continuous distillation of theformed ethanol.

The volatile components were removed by vacuum distillation at 25/0.5mm. The residue was triturated with methanol and the insoluble materialcrystallized from 600 ml. methanol to give 25.5 g. (58 percent) oftrans-B-dimethylamino-2,5-dimethyl-4-nitrostyrene as dark red needleshaving a melting point of l30-l 3 1.

Anal. Calcd. for C H M z;

7.32; Found: 7 29 The methanol triturate was evaporated and the residuedigested with petroleum ether X 100 ml.). The petroleum ether extractsyielded 14.5 g. of red solid which after dissolution in 50 ml. ofethanol was added to a solution of 140 g. of ferrous sulfateheptahydrate, 500 ml. of water, and 85 ml. of concentrated ammonia. Theresulting mixture was heated at reflux for 15 minutes, and theprecipitate which formed was removed by filtration. The filtrate wasconcentrated by evaporation and then extracted with carbon tetrachloride(3 X 200 ml.). The combined organic phases were dried (Na SO filtered,and evaporated. The residue was percolated through a dry column ofalumina with 5 percent benzene-hexane. The fractions were combined andthe solvents removed to give 450 mg. of a white solid. The material wascrystallized from 8 ml. of petroleum ether to give 277 mg. of 5,6-dimethylindole as white needles having a melting point of 64.565.5.

EXAMPLE 28 Preparation of trans-B-dimethylamino-5-fluoro-2- nitrostyreneA 250-ml. three-necked flask fitted with a thermometer and a 15-cm.Vigreux column connected to a descending condenser and receiver with anitrogen inlet was charged with 20.00 g. of 5-fluoro-2- nitrotoluene,56.0 g. of percent of N,N-dimethylformamide diethyl acetal, and ml. ofN,N-dimethylforrnamide. The reaction vessel was immersed in an oil bath,preheated to 160, for 3.5 hours. The pot temperature was maintainedabove by continuous distillation of the formed ethanol.

The volatile components were removed by vacuum distillation at 25/0.5mm., and the residual dark red solid was crystallized from 70 ml. ofether-petroleum ether to give 20.55 g. of red needles having a meltingpoint of 52-55. The mother liquor, after removal of the solvents anddistillation at l38140/0.1 mm. yielded an additional 4.24 g. of redsolid having a melting point of 5658. Total yield was 24.79 g. (92percent). A portion of the material was recrystallized to givetrans-B-dimethylamino-S-fluoro-2-nitrostyrene as red crystals having amelting point of 56-5 8.

Anal. Calcd. for C H FN O C, 57.14; H, 5.28 F, 9.03; N, 13.32 Found: C57.05;H, 5.36 F 8.72; N, 13.39

EXAMPLE 29 Preparation of 5-fluoroindole To a solution of 10.51 g. oftrans-B-dimethylamino- 5-fluoro-2-nitrostyrene in 250 ml. of benzene ina 500- ml. Parr bottle was added a half teaspoon of Raney nickel. Thesuspension was shaken under an initial hydrogen pressure of 3.5 atm.until the absorption of hydrogen ceased. The catalyst was removed byfiltration and washed several times with benzene. The benzene filtratewas then extracted with 3 X 100 ml. of 1M sulfuric acid, 2 X ml. ofwater, and 150 ml. of 10 percent sodium bicarbonate solution. Theaqueous phases were back-washed with 100 ml. of benzene in acounter-current manner. The combined benzene phases were dried (Na SOfiltered, and evaporated to give 5.23 g. of brown solid. Distillation(b.p. 85/0.5 mm.) yielded 5.01 g. of yellowish solid, which uponcrystallization from pentane yielded 2.36 g. of 5- fluoroindole as whiteleaflets having a melting point of 46.547. The mother liquor waspercolated through 10 g. of alumina and the product eluted with ether.sublimation of this material gave an additional 1.07 g. of producthaving a melting point of 4647. Thus, the total yield was 3.44 g. (51percent).

EXAMPLE 30 Preparation of trans-4-(B-dimethylaminovinyl)-3-nitrobenzaldehyde dimethyl acetal A 250-ml. three-necked flask fittedwith a thermometer and a 15-cm. Vigreux column connected to a descendingcondenser and receiver with a nitrogen inlet was charged with 11.18 g.of 4-methyl-3- nitrobenzaldehyde dimethyl acetal, 11.8 g. of N,N-dimethylformamide diethyl acetal, and 50 ml. of N,N-

dimethyl-formamide. The reaction vessel was immersed in an oil bath,preheated to 160, for 8 hours. The pot temperature was maintained above140 by continuous distillation of the formed ethanol.

The volatile components were removed by vacuum distillation at 25/0.5mm. The dark red solid residue was triturated with cold methanol. Theremaining solid was crystallized from 30 ml. of ether-pentane to obtain7.22 g. of trans-4-(B-dimethylamino-vinyl)-3- nitrobenzaldehydedimethyl'acetal having a melting point of 67-68.5. The residue, obtainedafter evaporation of the mother liquor, was crystallized from 5 ml. ofether-pentane to give an additional 0.57 g. of product having a meltingpoint of 66.5-68.0. Thus, the total yield was 7.79 g. (55 percent).

Anal. Calcd. for C H Np Found:

C, 58.63; H, 6.81; N, 10.52 C, 58.69; H, 6.75; N, 10.40

EXAMPLE 31 Preparation of 6-formylindole To a solution containing 5.31g. of trans-4-(B- dimethyl-aminovinyl)-3-nitrobenzaldehyde dimethylacetal in 250 ml: of benzene in a 500-ml. Parr bottle was added a halfteaspoon of Raney nickel. The suspension was shaken under an initialhydrogen pressure of EXAMPLE 32 Preparation of 6-formylindole dimethylacetal To a solution containing 6.65 g. of trans-4-(B-dimethylamino-vinyl)-3-nitrobenzaldehyde dimethyl acetal in 125 ml. ofbenzene were added 1.0 g. potassium carbonate and 0.332 g. of 10 percentpalladium on carbon. The suspension was stirred under an atmosphere ofhydrogen. After the hydrogen absorption ceased, the catalystwas removedby filtration and was washed several times with benzene. Evaporation ofthe filtrate gave 4.95 g. of residue which on short-path distillationyielded 1.74 g. of purplish oil, which crystallized on cooling.Crystallization of this solid from 10 ml. of ether-petroleum etheryielded 1.18 g. of white solid having a melting point of 6263.5. Themother liquor was applied to 10 g. of alumina and an additional 052 g.of the same product was eluted with 1:1 etherpetroleum ether.Recrystallization from ether-petroleum ether yielded 1.34 g. (27percent) of 6-formylindole dimethyl acetal having a melting point of6263.5

Anal.

Calcd. for C H,,NO,: C, 69.09; H, 6.35; N, 7.33 Found: C, 69.22; H,6.76; N, 7.34

EXAMPLE 33 Preparation of trans-4-(B-dimethylaminovinyl)-3-nitrobenzaldehyde A -ml. three-necked flask fitted with a refluxcondenser with a nitrogen inlet was charged with 8.25 g. of4-methyl-3-nitrobenzaldehyde, 11.1 g. of N,N- dimethylformamide diethylacetal, and 50 ml. of N,N- dimethylformamide. The reaction vessel wasimmersed in an oil bath, preheated to for 45 minutes.

The volatile components were removed by vacuum distillation at 25/0.5mm. The dark red residue was triturated three times with 10 ml. ofpetroleum ether. The solid residue gave, on crystallization frommethanol, 5.47 g. and on recrystallization from 100 ml. of methylenechloride-ether, 4.61 g. of trans-4-(B-dimethylaminovinyl)-3-nitrobenzaldehyde as red crystals having a meltingpoint of 134l36. The residue obtained from the mother liquors wascrystallized from 12 ml. of ethyl acetate to give an additional 2.21 g.of product having a melting point of 134l36. Thus, the total yield was6.81 g. (62 percent).

C, 59.99; H, 5.4 C, 60.23; H, 5.2

lEXAMPLE 34 Preparation of trans-B-dimethylamino-4-isopropyl-2-nitrostyrene In a 100-ml. three-necked flask fitted with a thermometerand 8-cm. Vigreux distillation head connected to a descending condenserand receiver with a nitrogen inlet were placed 17.9 g. of2-nitro-p-cymene, 17.9 g. of N,N-dimethylformamide dimethyl acetal, and25 ml. of N,N-dimethylformamide. The flask was immersed in a oil bathfor 42 hours, during which time 8 ml. of methanol distilled. Thecontents of the reaction vessel were transferred to a Claisen flask.Vacuum distillation, after removal of the more volatile components up to130/0.06 mm., afforded 19.61 g. (84 percent) oftrans-B-dimethylamino-4-isopropyl-2- nitrostyrene as a red liquid (b.p.138-140/0.06 mm.). An analytical sample obtained from a previousexperiment gave:

Anal. Calcd. for C HI N Og Found:

C, 66.64; H, 7. C, 66.69; H, 7.

EXAMPLE 35 Preparation of 6-isopropylindole A solution containing 11.71g. of trans-B- dimethylamino-4-isopropyl-2-nitrostyrene in 125 ml. ofbenzene and 0.234 g. of 10 percent palladium on carbon were stirredunder a hydrogen atmosphere. After hydrogen absorption ceased, thecatalyst was removed by filtration and was washed several times withAnal. Calcd. l OTC H NZ C, 8

2.97; Found: C, 83.20;

EXAMPLE 36 Preparation of trans-B-dimethylamino-4-methoxy-2-nitrostyrene In a 250-ml. three-necked flask fitted with a thermometer,a l5-cm. Vigreux column connected to a descending condenser and areceiver with a nitrogen inlet were placed 25.1 g. of4-methyl-3-nitroanisole, 42.0 g. of 88 percent N,N-dimethylformamidediethyl acetal, and 150 ml. of N,N-dimethylformamide. The flask wasimmersed in an oil bath, preheated to 165, for 70 hours. The pottemperature was maintained above 140 by continuous distillation of theformed ethanol.

The volatile components were removed by vacuum distillation undernitrogen until the head temperature rose above 95/0.05 mm. The remainingdark liquid was then transferred to a Claisen flask and distilled toyield 21.2 g. (64 percent) oftrans-B-dimethylaminoimethoxy-2-nitrostyrene as a dark red liquid havinga boiling point of 152/0.06 mm.

H, 8.23; N, 8.80 H, 8.23; N, 8.91

Anal. Calcd. for C H N,O,: C, 59.45; H, 6.35; N, 12.60 Found: C, 59.68;H, 6.53; N, 12.64

EXAMPLE 37 Preparation of 6-methoxyindole To a solution of 13.478 g. oftrans-B-dimethylamino- 4-methoxy-2-nitrostyrene in 250 ml. of benzene ina 500-ml. Parr bottle was added a half teaspoon of Raney nickel. Thesuspension was shaken under an initial hydrogen pressure of 3.5 atm.until hydrogen absorption ceased. The catalyst was removed by filtrationand was washed several times with benzene. The benzene filtrate was thenextracted with 2 X 100 ml. of 1M sulfuric acid, 2 X 100 ml. of water,and 100 ml. of 10 percent sodium bicarbonate solution. The aqueousphases were back-washed with 100 ml. of benzene in a counter-currentmanner. The combined benzene phases were dried (Na- SO filtered, andevaporated to give 6.7 g. of yellowish solid which, on distillation,yielded 5.64 g. (63 percent) of 6-methoxy-indole as an almost whitesolid having a melting point of 88-90.

EXAMPLE 38 Preparation of trans-B-dimethylamino-S-methoxy-2-nitrostyrene A 250-ml. three-necked flask fitted with a thermometer anda l5-cm. Vigreux column connected to a descending condenser and receiverwith a nitrogen inlet was charged with 16.7 g. of 5-methoxy-2-nitrotoluene, 32.3 g. of N,N-dimethylformamide diethyl acetal, and 100ml. of N,N-dimethylformamide. The reaction vessel was then immersed inan oil bath, preheated to 165, for 22 hours. The pot temperature wasmaintained above 140 by continuous distillation of the formed ethanol.

The volatile components were removed by vacuum distillation at 25/0.5mm. The resulting dark red solid residue was crystallized from ml. ofether and 75 m1. of petroleum ether, and yielded 17.0 g. of trans-B-dimethylamino-5-methoxy-2-nitrostyrene as red crystals having a meltingpoint of 67.5-69.5. The residue, obtained after evaporation of themother liquor, was triturated with 10 ml. of ice-cold methanol.Recrystallization of the resulting solid (2.8 g.) from 10 ml. ofmethanol gave an additional 2.7 g. of product having a melting point of6869. Thus, the total yield was 19.7 g. (89 percent).

Anal Calcd. for C H ,N,O;:

Found:

EXAMPLE 39 Preparation of trans-B-dimethylamino-S-methoxy-2-nitrostyrene A solution of 8.35 g. of 3-methyl-4-nitroanisole, 14.58 g.of N,N-dimethylformamide dineopentyl acetal, and 50 ml. ofN,N-dimethylformamide was heated at reflux under a nitrogen atmospherefor 41 hours and then was transferred to a Claisen flask. Vacuumdistillation gave, after removal of the volatile components, 4.75 g. ofa red liquid (b.p. 152/0.04 mm.) which crystallized on scratching togive a solid having a melting point of 61-65. Recrystallization from 70ml. of ether-petroleum ether gave 3.70 g. (33 percent) oftrans-B-dimethylamino-S-methoxy-2- nitrostyrene having a melting pointof 68.5-69.5.

EXAMPLE 40 C, 59.45; H,6.35;N, 12.60 C, $9.53; H,6.39;N, 12.65

EXAMPLE 41 Preparation of trans-B-dimethylamino-S-methoxy-2-nitrostyrene A solution of 16.71 g. of 3-methyl-4-nitroanisole, 30.00 g.of N,N-dimethylformamide dibenzyl acetal, and 50 m1. ofN,N-dimethylformamide was heated at reflux under a nitrogen atmospherefor 17 hours and then was transferred to a Claisen flask. Vacuumdistillation gave, after removal of the volatile components, 9.42 g. ofa red liquid (b.p. l58/0.l0 mm.) which gave a tacky solid uponscratching. Recrystallization from m1. of ether-petroleum ether gave7.15 g. (32 percent) of trans-B-dimethylamino-S-methoxy-2- nitrostyrenehaving a melting point of 68.069.5.

EXAMPLE 42 Preparation of trans-fi-dimethylamino-S-methoxy-Z-nitrostyrene A solution of 8.35 g. of 3-methyl-4-nitroanisole, 8.76 g.of N,N-dimethylformamide ethylene acetal (2-dimethylamino-l,3-dioxolane), and 25 ml. of N,N- dimethylformamide washeated at 150 under a nitrogen atmosphere for 53 hours and then wastransferred to a Claisen flask. Vacuum distillation gave, after removalof the volatile components, 4.00 g. of a red liquid (b.p. 149/0.07 mm.)which formed a gummy solid on scratching. Crystallization from 15 ml. ofmethanol gave 1.57 g. (14 percent) of trans-B-dimethylamino-S-methoxy-2-nitrostyrene having a melting point of 6869.

EXAMPLE 43 Preparation of trans-5-methoxy-2-nitro-B-pyrrolidinostyreneTo a 100-ml. three-necked flask fitted with a thermometer and 8-cm.Vigreux column connected to a descending condenser and receiver with anitrogen inlet was added 8.35 g. of 3-methyl-4-nitroanisole, 8.0 g. of N-formylpyrrolidine dimethyl acetal, and 25 ml. of N,N-dimethylformamide.The solution was heated at 135 for 2 hours with continuous distillationof the methanol which formed in the reaction.

Removal of the volatile components under vacuum (40 bath/1 mm.) andrecrystallization of the red residue from 75 ml. of methanol gave, intwo crops, 11.7 g. (94 percent) of red needles, melting point 7172.

Recrystallization of a portion of the first crop from methanol gave ananalytical sample of trans-S-methoxy-2-nitro-B-pyrrolidinostyrene,melting point 7172.

Anal. Calcd. for C H Nfl z C, 62.89; H, 6.50; N, 11.28 Found: C, 62.87;H, 6.58; N. 11.24

EXAMPLE 44 Preparation of S-methoxyindole To a solution containing 11.11g. of trans-B- dimethylamino 5-methoxy-2-nitrostyrene in 250 ml. ofbenzene in a SOO-ml. Parr bottle was added 230 mg. of 10 percentpalladium on carbon. The suspension was shaken under an initial hydrogenpressure of 3.5 atm. until the absorption of hydrogen had ceased. Thecatalyst was removed by filtration and was washed several times withbenzene. The benzene filtrate was then extracted with 2 X 100 ml. of 1Msulfuric acid, 2 X 100 ml. of water, and 100 ml. of 10 percent sodiumbicarbonate solution. The aqueous phases were backwashed with 100 ml. ofbenzene in a counter-current manner. The combined benzene phases weredried (Na SO filtered and evaporated to give 5.45 g. of a brown solid.Distillation yielded 5.26 g. (72 percent) of S-methoxyindole as aslightly yellowish liquid, having a boiling point of 108/0.3 mm., whichcrystallized on cooling to an off-white solid having a melting point of5657.

EXAMPLE 45 preparation of 4,5-methylenedioxy-2-nitrotoluene A solutioncontaining 75.0 g. of piperonal, 200 ml. of glacial acetic acid, and 1ml. of cone. hydrochloric acid was shaken with 4 g. of 10 percentpalladium on carbon in an autoclave under an initial hydrogen pressureof 35 atm. until hydrogen absorption ceased. The catalyst was removed byfiltration.

The filtrate was transferred to a three-neck flask fitted with athermometer, mechanical stirrer, and a dropping funnel. A solutioncontaining 80.0 ml. of cone. nitric acid in 200 ml. of glacial aceticacid was added to the reaction vessel with stirring over a period of 1hour. The reaction vessel was maintained below 10 by means of anice-acetone bath. After the addition was complete, the reaction mixturewas allowed to reach room temperature and was then poured over a mixtureof sodium hydroxide and ice. The resulting suspension was extracted withmethylene chloride (4 X 1000 ml.). The combined organic phases weredried (Na SO filtered, and evaporated to give a yellow solid, whichafter crystallization from 300 ml. of ethanol, gave 76.5 g. (84 percent)of 4,5- methylenedioxy-Z-nitrotoluene as yellow needles having a meltingpoint of 85-86.5.

EXAMPLE 46 Preparation of trans-B-dimethylamino-4,5-methylenedioxy-2-nitro-styrene A 250-ml. three-necked flask fitted witha thermometer and a l5-cm. Vigreux column connected to a descendingcondenser with a receiver and a nitrogen inlet was charged with 18.1 g.of 4,5-methylenedioxy-2- nitrotoluene, 20 g. of N,N-dimethylformamidediethyl acetal, and ml. of N,N-dimethylformamide. The reaction vesselwas immersed in a 165 oil bath for 17.5 hours. The pot temperature wasmaintained above 140 by continuous distillation of the formed ethanol.

The volatile components were removed by vacuum distillation at 25/0.05mm. The residue was crystallized from 300 ml. of ethanol to give 17.0 g.(72 percent) of trans-B-dimethylamino-4,S-methylenedioxy-Z- nitrostyreneas red-brown crystals having a melting point of 1l4116.

C, 55.93; H, 5.12; N, 11.86 C, 56.09; H, 5.17; N, 11.56

EXAMPLE 47 Preparation of 5,6-methylenedioxyindole A solution containing11.83 g. of trans-B- dimethylamino-4,5-methylen'edioxy-2-nitrostyrene in250 ml. of benzene was shaken with 1 teaspoonful of Raney nickel underan initial hydrogen pressure of 3.5 atm. until hydrogen absorptionceased. The catalyst was removed by filtration and washed several timeswith benzene. The filtrate and washings were washed with 1M sulfuricacid (2 X 100 ml.), 100 ml. of water, and 100 ml. of 10 percent sodiumbicarbonate. The combined organic phases were dried (Na SO filtered andevaporated to give 5.52 g. of a brown solid. A solution of the residuein benzene was percolated through a column of alumina. The eluate, afterevaporation of the solvent, was sublimed at /0.2 mm. to give 5.2 g. of awhite solid which, upon crystallization from methylene chloride-hexane,yielded 4.50 g. (50 percent) of 5,6-methylenedioxyindole as whiteneedles having a melting point of l09.5l 10.5".

EXAMPLE 48 Preparation of trans-B-dimethylamino-t')-methyl-2-nitrostyrene A 250-ml. three-necked flask fitted with a thermometer anda IS-cm. Vigreux column connected to a descending condenser and receiverwith a nitrogen inlet was charged with 15.22 g. of 3-nitro-o-xylene,20.00 g. of N,l l-dimethylformamide diethyl acetal, and l ml. ofN,N-dimethylformamide. The reaction vessel was immersed in an oil bath,preheated to 160, for 24 hours. The pot temperature was maintained abovel40 by continuous distillation of the formed ethanol.

The volatile components were removed by vacuum distillation until thehead temperature began to rise above 90/0.l mm. Further distillationyielded 14.54 g. (70 percent) of trans-B-dimethylamino-6-methyl-2-nitrostyrene as a dark red liquid having a boiling point of l08/0.05 mm.

C,64.06; H,6.84;N, 13.58 C,63.79; H,7.28;N, 13.71

EXAMPLE 49 Preparation of 4-methylindole To a solution containing 9.327g. of trans-B- dimethylamino-6-methyl-2-nitrostyrene in 250 ml. ofbenzene in a 500-ml. Parr bottle was added a half teaspoon of Raneynickel. The suspension was shaken under an initial hydrogen pressure of3.5 atm. until the absorption of hydrogen had ceased. The catalyst wasremoved by filtration and washed several times with benzene. The benzenefiltrate was then extracted with 2 X 100 ml. of 1M sulfuric acid, 2 X100 ml. of water, and 100 ml. of percent sodium bicarbonate solution.The aqueous phases were back-washed with 150 ml. of benzene in acounter-current manner. The combined benzene phases were dried (Na SOfiltered, and evaporated to give 3.89 g. of a brown oil which after twodistillations yielded 3.37 g. (57 percent) of 4- methylindole as ayellow liquid having a boiling point of 82/0.4 mm.

EXAMPLE 50 Preparation of trans-B-dimethylamino-3-methyl-2- nitrostyreneA 500-ml. three-necked flask fitted with a thermometer, a l5-cm. Vigreuxcolumn connected to a descending condenser and receiver with a nitrogeninlet was charged with 30.23 g. of 2-nitro-m-xylene, 64.77 g. ofN,N-dimethylformamide diethyl acetal, and 200 ml. of N,lldimethylformamide. The reaction vessel was then immersed in an oilbath, preheated to 165, for 46 hours. The pot temperature was maintainedabove l40 by continuous distillation of the formed ethanol.

The volatile components were removed by vacuum distillation at 25/0.5mm. The resulting dark red liquid residue was distilled under vacuum,the forerun (15.32 g., b.p. 93-99/0.02 mm.) was a mixture of trans-B-dimethylamino-3-methyl-2-nitrostyrene and 2-nitro-mxylene (ratio of 3:5resp.). Subsequent fractions yielded 16.60 g. (40 percent) of trans-B-dimethylamino-3-methyl-2-nitrostyrene as a red liquid (b.p. ll6-ll7/0.04 mm.) which crystallized on cooling and had a melting point of77.

Analv Calcd. for C,,H N,O,: C, 64.06; H, 6.84; N, 13.58 Found: C,63.95;H,6.70;N, 13.37

EXAMPLE 51 Preparation of 7-methylindole To a solution containing 10.31g. of trans-B- dimethylamino-3-methyl-2-nitrostyrene in 250 ml. ofbenzene was added 103 mg. of 10 percent palladium on carbon. Thesuspension was shaken under an initial hydrogen pressure of 3.5 atm.until the absorption of hydrogen had ceased. The catalyst was removed byfiltration and was washed several times with benzene. The benzenefiltrate was then extracted with 2 X ml. of 1M sulfuric acid, 100 ml. ofwater, and 100 ml. of 10 percent sodium bicarbonate solution. Theaqueous phases were back-washed with l00 ml. of benzene in acounter-current manner. The combined benzene phases were dried (Na SOfiltered and evaporated to give 4.628 g. of residue which, ondistillation under vacuum, gave 4.203 g. (b.p.'l09/0.9 mm.) oflight tanksolid. Filtration of the distillate through 50 g. of alumina andcrystallization from 30 ml. of ether-petroleum ether gave 3.15 g. (48percent) of 7-methylindole as white crystals having a melting point of8384.

EXAMPLE 52 Preparation of trans-B-dimethylamino-4,5-dimethoxy-2-nitrostyrene A l-l. three-necked flask fitted with a thermometer and alS-cm. Vigreux column connected to a descending condenser with areceiver and nitrogen inlet was charged with 98.6 g. of4,5-di-methoxy-2-nitrotoluene, 500 ml. of N,N-dimethylformamide, and g.of N,N- dimethyformamide dimethyl acetal. The reaction temperature wasmaintained at for 42 hours. The volatile compounds were removed byvacuum distillation at 25/0.l mm. to give a solid residue of crudetrans-B-dimethylamino-4,5-dimethoxy-2-nitr0styrene.

From a previous experiment, an analytical sample oftrans-B-dimethylamino-4,5-dimethoxy-2-nitrostyrene, a red solid, mp.l25l 26, was obtained by crystallization from methanol.

Anal. Calcd. for C ,H, N,O C,57.l3; H,6.39;N,ll.ll Found: C,57.47;H,6.65;N, 11.35

EXAMPLE 53 Preparation of 5,6-dimethoxyindole To a solution of the crudetrans-B-dimethylamino- 4,5-dimethoxy-2-nitrostyrene obtained in Example52 in 2.0 l. of benzene was added 10 g. of l0 percent palladium oncarbon, and the suspension was shaken under an initial hydrogen pressureof 7 atm. After hydrogen absorption ceased (3 equivalents), the catalystwas filtered and washed with 2 l. of benzene. The combined filtrate andwashings were concentrated to 2.1. in vacuo and the organic phase washedwith 3 X 300 ml. of 1N sulfuric acid, 200 ml. of 1N sodium hydroxide and200 ml. of water. The aqueous phases were back-washed in acounter-current manner with 500 ml. of benzene. The combined organicphases were dried (Na SO,) and filtered through 280 g. of silica gel.The filtrate was evaporated and the residue triturated with ether. Theresidual white solid was crystallized from 700 ml. of benzene to give(in two crops) 24.5 g.

(28 percent) of 5,6-dimethoxyindole as white crystals, m.p. 154-l55.

EXAMPLE 54 Preparation of trans-4,5-dibenzyloxy-B-dimethylamino-Z-nitro-styrene In a l-l. three-necked flask fitted with athermometer and 8-cm. Vigreux distillation head connected to adescending condenser and receiver with a nitrogen inlet were placed 87.3g. of 4,5-dibenzyloxy-2- nitrotoluene, 38.0 g. of N,N-dimethylformamidedimethyl acetal, and 250 ml. of N,N-dimethylformamide. The solution washeated at 140 for 48 hours with continuous removal of the methanol as itformed. The volatile components were removed by vacuum distillation(bath temperature 65/0.l mm.). Crystallization of the residue frommethanol (2.5 1.) yielded (two crops) 86.8 g. (86 percent) of red solid,mp. 99l00.

An analytical sample, obtained from a previous experiment, wascharacterized as trans-4,5-dibenzyloxy- B-dimethylamino-2-nitrostyrene,m.p. 99.5-101.

Anal. Calcd. for C,,H N O,: C, 71.27, H, 5.98; N, 6.93 Found: C,7l.09;H,6.30;N,6.83

EXAMPLE 55 Preparation of 5,6-dibenzyloxyindole To a solution of 10.11g. of trans-4,5-dibenzyloxy-B- dimethylamino-Z-nitrostyrene in 250 ml.of benzene in a 500-ml. Parr bottle was added a teaspoon of Raneynickel. The suspension was shaken under an initial hydrogen pressure of3.5 atm. until the absorption of hydrogen ceased. The catalyst wasremoved by filtration and washed several times with benzene. The benzenefiltrate was extracted with 3 X 100 ml. of 1N sulfuric acid, 250 ml. ofwater, 3 X 100 ml. of 1N sodium hydroxide and 250 ml. of water. Theaqueous phases were back-washed in a countercurrent manner with 100 ml.of benzene.

The combined organic phases were dried (Na SO,), filtered and evaporatedto give 7.67 g. of a brown solid which was dissolved in a minimum amountof benzene and was chromatographed on 40 g. of silica gel prepared inhexane. Eluted fractions [benzene-hexane (1:1)] were pooled according tothin layer chromatography. Evaporation of the solvents andrecrystallization of the residue (5.8 g.) from benzene-hexane yielded4.34 g. (54 percent) of 5,6-dibenzyloxyindole as white needles, mp.ll2-l13.

We claim l. A process for preparing indoles of the formula wherein R andR individually, are hydrogen; lower alkyl; phenyl; phenyl bearing one ormore substituents selected from the group consisting of halogen,trifluoromethyl, lower alkyl, lower alkoxy, nitro, amino, loweralkylamino and di-lower alkylamino; hydroxy; lower alkoxy; phenyl-loweralkoxy; phenyllower alkoxy wherein the phenyl group bears one or moresubstituents selected from the group consisting of halogen,trifluoromethyl, lower alkyl, lower alkoxy, nitro, amino, loweralkylamino and di-lower alkyl; phenoxy; phenoxy wherein the phenyl groupbears one or more substituents selected from the group consisting ofhalogen, trifluoromethyl, lower alkyl, lower alkoxy, nitro, amino, loweralkylamino and di-lower alkyl; lower alkanoyloxy; benzoyloxy; formyl;benzoyl; hydroxymethyl; phenyl-hydroxymethyl; phenylhydroxymethylwherein the phenyl group bears one or more substituents selected fromthe group consisting of halogen, trifluoromethyl, lower alkyl, loweralkoxy, nitro, amino, lower alkylamino and di-lower alkyl; carboxy;lower alkoxycarbonyl; carbamoyl; halogen; cyanoj nitro; amino;mono-lower alkylamino; di-lower alkylamino; lower alkoxycarbonylamino;phenyl-lower alkoxycarbonylamido; phenyl-lower alkoxycarbonylaminowherein the phenyl group bears one or more substituents selected fromthe group consisting of halogen, trifluoromethyl, lower alkyl, loweralkoxy, nitro, amino, lower alkylamino and di-lower alkyl; loweralkanoylamino; benzoylamino; N-lower alkyllower alkanoylamino; N-loweralkylbenzoylamino; di lower alkylformamidino; or di-lower alkoxymethyl;and when taken together, are lower alkylenedioxy which comprisescondensing an ortho-nitrotoluene of the formula wherein R, and R are asdescribed above, with formamide acetals of the formula V III IVa

wherein R R R and R are as previously described with a reducing agent toyield the corresponding indole.

2. A process for preparing indoles of the formula wherein R and Rindividually, are hydrogen; lower alkyl; phenyl; phenyl bearing one ormore substituents selected from the group consisting of halogen,trifluoromethyl, lower alkyl, lower alkoxy, nitro, amino, loweralkylamino and di-lower alkylamino; hydroxy; lower alkoxy; phenyl-loweralkoxy; phenyllower alkoxy wherein the phenyl group bears one or moresubstituents selected from the group consisting of halogen,trifluoromethyl, lower alkyl, lower alkoxy, nitro, amino, loweralkylamino and dilower alkyl; phenoxy; phenoxy wherein the phenyl groupbears one or more substituents selected from the group consisting ofhalogen, trifluoromethyl, lower alkyl, lower alkoxy, nitro, amino, loweralkylamino and di-lower alkyl; lower alkanoyloxy; benzoyloxy; formyl;benzoyl; hydroxymethyl; phenylhydroxymethyl; phenyl-hydroxymethylwherein the phenyl group bears one or more substituents selected fromthe group consisting of halogen, trifluoromethyl, lower alkyl, loweralkoxy, nitro, amino, lower alkylamino and di-lower alkyl; carboxy;lower alkoxycarbonyl; carbamoyl; halogen; cyano; nitro; amino;mono-lower alkylamino; di-lower alkylamino; lower alkoxycarbonylamino;phenyl-lower alkoxycarbonylamino; phenyl-lower alkoxycarbonylaminowherein the phenyl group bears one or more substituents selected fromthe group consisting of halogen, trifluoromethyl, lower alkyl, loweralkoxy, nitro, amino, lower alkylamino and di-lower alkyl; loweralkanoylamino; benzoylamino', N-lower alkyllower alkanoylamino; N-loweralkylbenzoylamino; dilower alkylformamidino; or di-lower alkoxymethyl,and when taken together, are lower alkylenedioxy which comprisestreating a compound of the formula NO: 1V8.

wherein R and R are as previously described,

and R and R independently, are lower alkyl,

and when taken together, are lower alkylene, with a reducing agent.

3. A process in accordance with claim 2, wherein the formamide acetal isN,N-di-lower alkylformamide dilower alkyl acetal.

4. A process in accordance with claim 3, wherein the condensation iscarried out in a polar aprotic solvent.

5. A process in accordance with claim 4, wherein the polar aproticsolvent is N,N-dimethylfonnamide.

6. A process in accordance with claim 5, which comprises condensingo-nitrotoluene with N,N-dimethylformamide dimethyl acetal and reducingthe resulting trans-B-dimethylamino-2-nitrostyrene to yield indole.

7. A process in accordance with claim 2 which comprises treatingtrans-B-dimethylamino-2-nitrostyrene with a reducing agent to yieldindole.

8. A process in accordance with claim 2 which comprises treatingtrans-2-nitro-B-piperidinostyrene with a reducing agent to yield indole.

9. A process in accordance with claim 2 which comprises treatingtrans-2-nitro-B-pyrrolidinostyrene with a reducing agent to yieldindole.

10. A process for preparing a compound having an indole nucleus whichcomprises simultaneously reducing the nitro function and removing theN,N-di-substituted amino function of a nitrobenzene derivative having aN,N-di-substituted aminovinyl function ortho to the nitro group.

11. A process in accordance with claim 10, wherein the nitrobenzenederivative having a N,N-di-substituted aminovinyl function is obtainedby condensing the methyl function of an orthonitrotoluene with theformyl group of a formamide acetal.

12. A process for preparing an indole which comprises condensing anortho-nitrotoluene of the formula wherein R R R and R independently, areselected from the group consisting of hydrogen; lower alkyl; phenyl;phenyl bearing one or more substituents selected from the groupconsisting of halogen, trifluoromethyl, lower alkyl, lower alkoxy,nitro, amino, lower alkylamino and dilower alkylamino; hydroxy; loweralkoxy; phenyllower alkoxy; phenyllower alkoxy wherein the phenyl groupbears one or more substituents selected from the group consisting ofhalogen, trifluoromethyl, lower alkyl, lower alkoxy, nitro, amino, loweralkylamino and di-lower alkyl; phenoxy; phenoxy wherein the phenyl groupbears one or more substituents selected from the group consisting ofhalogen, trifluoromethyl, lower alkyl, lower alkoxy, nitro, amino, loweralkylamino and di-lower alkyl; lower alkanoyloxy; benzoyloxy; formyl;benzoyl; hydroxymethyl; phenyl-hydroxymethyl; phenylhydroxy methylwherein the phenyl group bears one or more substituents selected fromthe group consisting of halogen, trifluoromethyl, lower alkyl, loweralkoxy, nitro, amino, lower alkylamino and di-lower alkyl; carboxy;lower alkoxycarbonyl; carbamoyl; halogen; cyano; nitro; amino;mono-lower alkylamino; di-lower alkylamino; lower alkoxycarbonylamino;phenyl-lower alkoxycarbonylamino; phenyl-lower alkoxycarbonylaminowherein the phenyl group bears one or more substituents selected fromthe group consisting of halogen, trifluoromethyl, lower alkyl, loweralkoxy, nitro, amino, lower alkylamino and di-lower alkyl; loweralkanoylamino; benzoylamino; N-lower alkyllower alkanoylamino; N-loweralkylbenzoylamino; dilower alkylformamidino; or di-lower alkoxymethyl; Rand R or R and R or R and R when taken together, are loweralkylenedioxy, with a formamide acetal and reducing the resultingortho-nitro-B-aminostyrene to obtain the desired indole.

13. A process in accordance with claim 6, wherein the reduction iseffected utilizing hydrogen and a catalyst selected from the groupconsisting of chromium, molybdenum, tungsten, platinum, palladium,rhodium, cobalt, nickel, ruthenium, their oxides, and combinationsthereof.

14. A process in accordance with claim 13, wherein the catalyst ispalladium.

15. A process in accordance with claim 2, wherein R and R are hydrogen.

16. A process in accordance with claim 2, which comprises treatingtrans-B-dimethylamino-Z- nitrostyrene,trans-2-nitro-B-piperidinostyrene, or trans-2-nitro-B-pyrrolidinostyrenewith hydrogen and a 29 3% catalyst selected from the group consisting ofchromirhodium, cobalt, nickel, ruthenium, their oxides and um,molybdenum, tungsten, platinum, palladium, combinations thereof.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION 0 PATENT NO. 13,732,245

DATED I May 8, 1973 INVENTO I Andrew David Batcho & Willy Leimgruber Itis certified that error appears in the above-identified patent and thatsaid Letters Patent Q are hereby corrected as shown below:

Column 26, claim 1, lines 4549 HC -OR I III 0 LIT-R7 should be: Q

o HC-OR III 0 Signed and Scaled this thirteenth Day of 197 [SEAL]Arrest:

RUTH C. MASON Altesting Officer C. MARSHALL DANN (um mr'ssimivr ofParents and Trademarks

2. A process for preparing indoles of the formula
 3. A process inaccordance with claim 2, wherein the formamide acetal is N,N-di-loweralkylformamide di-lower alkyl acetal.
 4. A process in accordance withclaim 3, wherein the condensation is carried out in a polar aproticsolvent.
 5. A process in accordance with claim 4, wherein the polaraprotic solvent is N,N-dimethylformamide.
 6. A process in accordancewith claim 5, which comprises condensing o-nitrotoluene withN,N-dimethylformamide dimethyl acetal and reducing the resulting trans-Beta -dimethylamino-2-nitrostyrene to yield indole.
 7. A process inaccordance with claim 2 which comprises treating trans- Beta-dimethylamino-2-nitrostyrene with a reducing agent to yield indole. 8.A process in accordance with claim 2 which comprises treatingtrans-2-nitro- Beta -piperidinostyrene with a reducing agent to yieldindole.
 9. A process in accordance with claim 2 which comprises treatingtrans-2-nitro- Beta -pyrrolidinostyrene with a reducing agent to yieldindole.
 10. A process for preparing a compound having an indole nucleuswhich comprises simultaneously reducing the nitro function and removingthe N,N-di-substituted amino function of a nitrobenzene derivativehaving a N,N-di-substituted aminovinyl function ortho to the nitrogroup.
 11. A process in accordance with claim 10, wherein thenitrobenzene derivative having a N,N-di-substituted aminovinyl functionis obtained by condensing the methyl function of an ortho-nitrotoluenewith the formyl group of a formamide acetal.
 12. A process for preparingan indole which comprises condensing an ortho-nitrotoluene of theformula
 13. A process in accordance with claim 6, wherein the reductionis effected utilizing hydrogen and a catalyst selected from the groupconsisting of chromium, molybdenum, tungsten, platinum, palladium,rhodium, cobalt, nickel, ruthenium, their oxides, and combinationsthereof.
 14. A process in accordance with claim 13, wherein the catalystis palladium.
 15. A process in accordance with claim 2, wherein R1 andR2 are hydrogen.
 16. A process in accordance with claim 2, whichcomprises treating trans- Beta -dimethylamino-2-nitrostyrene,trans-2-nitro- Beta -piperidinostyrene, or trans-2-nitro- Beta-pyrrolidinostyrene with hydrogen and a catalyst selected from the groupconsisting of chromium, molybdenum, tungsten, platinUm, palladium,rhodium, cobalt, nickel, ruthenium, their oxides and combinationsthereof.